Major depressive disorder is accompanied by dysfunctional cognitive and neuroendocrine processing of stressful information. The neurocircuitry underlying aberrant stress processing remains to be elucidated. Human imaging data and rodent stress studies suggest that limbic cortical regions are well-positioned to mediate hypothalamic-pituitary-adrenocortical (HPA) axis pathology seen in depression. The current proposal uses a functional/anatomical approach to test the hypothesis that limbic cortical regions, including the prelimbic and infralimbic cortices, use separate yet complementary mechanisms to integrate psychological and physiological stimuli into appropriate stress responses. The neuroendocrine and mood changes seen in depression likely reflect a failure of these cortical regions to appropriately interpret relevant stressful stimuli. This hypothesis will be tested in four Specific Aims. Aim 1 will use anatomical approaches to delineate monosynaptic and multisynaptic neural pathways connecting limbic cortices with hypothalamic stress effectors. Aim 2 will use lesion and stimulation approaches to test the necessity and sufficiency of defined limbic cortical subregions in inhibiting responses to psychological vs. physiological stressors. Aim 3 tests the involvement of specific limbic cortical-hypothalamic and limbic cortical-hippocampal circuits in mediating responses to stress, using a combined lesion-stimulation design. Finally, Aim 4 tests for interactions between limbic cortices and other limbic stress-regulatory regions, to determine whether limbic stress integration involves convergent projections or separate `labeled lines' to the hypothalamus. These studies are expected to identify limbic cortical circuits and mechanisms involved in stress integration, and thereby provide clear neuroanatomical targets for development of improved behavioral/pharmacological interventions for depression and other stress- related disease states. The medial prefrontal cortex is implicated in stress-related diseases, such as depression and PTSD. This proposal is designed to delineate neurocircuit mechanisms of stress control by this region. The project will shed new light on the role of the prefrontal cortex in stress processing, and identify anatomical and neurochemical targets for intervention in stress-related pathologies.